The present invention relates to febrifugine, isofebrifugine, and a method for producing the same.
Febrifugine and isofebrifugine derived from Chinese hydrangea are known to have strong activities against tropical malarial protozoan.
The chemical structures of febrifugine and isofebrifugine, known to show such strong activities against malarial protozoan, were reported to be represented by Formulas (A0) and (B0): 
Although the activity of these febrifugine compounds have been known from old times as active ingredients of Chinese medicines such as xe2x80x9cJOSANxe2x80x9d, practical isolation and utilization of these compounds have been difficult due to their rarity in nature, and efforts to develop an efficient method for synthesizing them under gentle conditions have not been successful.
Therefore, extensive investigations have been desired, from the viewpoint of efficient synthesis of febrifugines, including the synthesis of analogues, and the view point of the stereochemistry which enables the exertion of bioactivity.
Thus, the objective of the present invention is to thoroughly reinvestigate the basis of such strong activity against malarial protozoan in relation with its stereochemistry, to identify actual substances which exhibit extremely strong activity against tropical malarial protozoan, and to establish a total synthetic route which allows efficient large scale synthesis, by overcoming such conventional circumstances.
In order to accomplish the above objectives, the present invention provides, firstly, a febrifugine represented by Formula (A): 
Secondly, provided by the present invention is an isofebrifugine represented by Formula (B): 
Thirdly, a febrifugine or an isofebrifugine according to the first or second invention, having an anti-malarial activity is also provided.
Further, as the forth invention, an anti-malarial agent containing, as an active ingredient, a febrifugine or an isofebrifugine according to the first or second invention is also provided.
Furthermore, the present invention provides the following production methods. That is, as the fifth invention, a method for producing febrifugine wherein an S-aldehyde compound represented by Formula (C): 
(wherein R1 represents a silyl group and R2 represents a hydrocarbon group) is subjected to a Mannich reaction with a 2-alkoxyaniline compound and a 2-alkoxypropane compound in the presence of an aqueous Lewis acid of a rare earth metal, in an aqueous solvent, to form a diastereomeric mixture of a xcex2-aminoketone compound represented by Formula (D): 
(wherein R1 and R2 are defined as described above, and R3 represents a hydrocarbon group which forms an alkoxy group of the 2-alkoxyaniline described above), after which the anti-diastereomer is cyclized to form a pyperidine compound, and reacted with a quinazoline compound to obtain a febrifugine represented by Formula (A): 
As the sixth invention, a method for producing isofebrifugine wherein an S-aldehyde compound represented by Formula (C): 
(wherein R1 represents a silyl group and R2 represents a hydrocarbon group) is subjected to a Mannich reaction with a 2-alkoxyaniline compound and a 2-alkoxypropane compound in the presence of an aqueous Lewis acid of a rare earth metal, in an aqueous solvent, to form a diastereomeric mixture of a xcex2-aminoketone compound represented by Formula (D): 
(wherein R1 and R2 are defined as described above, and R3 represents a hydrocarbon group which forms an alkoxy group of the 2-alkoxyaniline described above), after which the syn-diastereomer is cyclized to form a pyperidine compound, and reacted with a quinazoline compound to obtain a isofebrifugine represented by Formula (B): 
is also provided.
Provided as the seventh invention is a method for producing a febrifugine or an isofebrifugine according to the fifth or sixth invention, wherein a silyloxypropanal represented by Formula (E): 
(wherein R1 represents a silyl group) and an ethene compound represented by Formula (F): 
(wherein R2 and R4 each represents a hydrocarbon group and R5 represents a silyl group) are subjected to an asymmetric aldol condensation in the presence of a chiral tin (II) Lewis acid catalyst, to form an addition reaction product represented by Formula (G): 
(wherein R1, R2 and R4 are defined as described above), dehydroxylated, and reduced to form an aldehyde compound of Formula (C), which is then subjected to a Mannich reaction.
Furthermore, as the eighth invention, a method for producing febrifugine or isofebrifugine according to the fifth or sixth invention, wherein an aldehyde compound represented by Formula (C) is reacted with a 2-alkoxydianiline compound and a 2-alkoxypropene compound by a Mannich reaction in water, in the presence of a Lewis acid-surfactant-integrated catalyst to form a xcex2-aciketone compound, is provided.
As described above, the present invention provides, by investigating extensively the product obtained through the established novel production method, novel substances represented by the above Formulas (A) and (B), as febrifugine and isofebrifugine expressing strong activity against tropical malarial protozoan.
Moreover, the present invention provides a production method which enables convenient and efficient large scale production of such novel substances.
While the aspects of the invention are as stated above, the embodiments of the invention are as described below.
First, a febrifugine and an isofebrifugine according to the invention may be specified as (2xe2x80x2R, 3xe2x80x2S)-febrifugine represented by Formula (A) and (2xe2x80x2S, 3xe2x80x2S)-isofebrifugine represented by Formula (B), respectively, and are distinct in terms of their absolute configuration, from conventional (2xe2x80x2S, 3xe2x80x2R)- and (2xe2x80x2R, 3xe2x80x2R)-compounds represented by the above Formulas (A0) and (B0).
Next, in the production of such compounds according to the present invention, an S-aldehyde compound represented by the above Formula (C), is the first key intermediate in the synthetic route. The second key intermediate is a xcex2-aminoketone compound represented by the above Formula (D).
The symbol Rxe2x80x2 in Formulas (C), (D), (E), (F) and (G) represents a silyl group which may be a hydrocarbon group, same or different, bonded to an Si atom. Examples of a trialkylsilyl group may be t-butyldimethylsilyl, trimethylsilyl groups and so on. R2 may be any one of various hydrocarbon groups which form protective groups. An example would be a benzyl group. R3 may also be any hydrocarbon group, such as an alkyl group including methyl, ethyl, and so on. R4 is also a hydrocarbon. An example would be a phenyl group. R5 is a silyl group, which may vary as described for Rxe2x80x2.
An aldol addition product (G) from which an aldehyde compound (C) is derived, is produced by an asymmetric aldol reaction, in which a chiral metal compound obtained from a metal compound and a chiral compound may be employed as a catalyst. For example, a chiral metal compound catalyst obtained from a triflate or perchlorate such as tin (II), and a chiral amine compound is useful.
The reaction may also be performed in an organic solvents such as ethers and nitrites.
One which is especially useful is a chiral tin (II) catalyst.
Also, the Mannich reaction by which compound (D) is derived from the above compound (C), may be performed in the presence of an aqueous Lewis acid catalyst of a rare earth metal.
For example, a triflate or a perchlorate of a rare earth metal such as ytterbium (Yb) and scandium (Sc) may be used.
Furthermore, a Lewis acid-surfactant-integrated catalyst may be employed in the Mannich reaction described above. Such catalyst may be any of the various salts of transition metals with surfactant compounds, such as scandium dodecylsulfate (STDS) obtained by mixing scandium chloride and sodium dodecylsulfate in water, as well as sulfonate compounds. The reaction may be performed in water, and the procedures are very simple.
The embodiments of the present invention are further described in reference to the following Examples. These Examples are not intended to restrict the invention in any sense. It is also a matter of course that a reaction method known per se may be employed in any relevant step.